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Chemical approaches to selectively target beta-rich amyloids

Award Number: R01AG074570
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Chemical approaches to selectively target beta-rich amyloids - PROJECT ABSTRACT Protein-protein interactions are governed by recognition events between peptide secondary structures (a- helices, b-sheets, loops), which in turn provide design cues for the development of selective chemical probes. However, removal of ordered peptide domains from the context of the surrounding tertiary structure compromises folding and conformational stability. Mimicry and disruption of b-strand/sheet interactions remains a considerable challenge. This is largely due to the inherent flexibility of short peptide sequences, the propensity for b-strands to aggregate, and the large surface areas and diverse modes of b-sheet packing. The early oligomerization of several amyloidogenic proteins involves conformational reorganization into parallel b-sheet structures, followed supramolecular assembly into toxic fibrils. Recent atomic-level structural data using patient-derived extracts has revealed that neurotoxic amyloids may be characterized by unique structural polymorphs, or ‘strains’, depending on the disease. Despite the need for amyloid- and strain-specific ligands, b-rich amyloid assemblies represent particularly challenging targets. We recently established peptide backbone N-amination as a subtle yet remarkably effective approach to b-strand/sheet stabilization. The conformational and non-aggregating characteristics of N-amino peptides (NAPs) render them uniquely suited for capping the growth of sheet fibrils while maintaining the facial packing and sidechain interdigitation important for amyloid recognition. Here, we will further develop soluble mimics of diverse b-sheet-like folds to disrupt amyloid aggregation in a sequence and strain-specific manner. As a proof-of-concept, we will target the assembly and cellular transmission of tau fibrils that characterize numerous sporadic and hereditary neurodegenerative disorders. Our overarching hypothesis is that the structural features of peptide N-amination will enable the development of ligands that selectively target b-rich amyloid folds. In Aim 1 we will expand the utility of NAP modification in pursuit of hyperstable b-strands and amyloid mimics based on parallel b-sheet macrocycles. A library of NAP-based tau mimics will be synthesized in Aim 2. These compounds will be evaluated for their ability to block aggregation and cellular transmission of recombinant tau fibrils as well those extracted from AD patients. In Aim 3, we will synthesize a series of aggregation-resistant NAP macrocycles that mimic the cross-b packing observed in pathogenic tau strains. These will be evaluated for their capacity to specifically inhibit cellular seeding by tau fibrils derived from AD and CBD brains. We anticipate that ligands emerging from this study will enable a robust examination of the the pathogenic strain model of tau transmission. More broadly, these studies will have a significant impact on the design of other selective disruptors of b-sheet and amyloid assemblies that are inherently difficult to target.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $471,616 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	001	5	6/5/2025	NON-COMPETING CONTINUATION	$471,616
2025	2024	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	000	4	5/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $471,616

Issue Date FY: 2024 ( Subtotal = $548,192 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	002	4	7/5/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	000	4	5/16/2024	NON-COMPETING CONTINUATION	$481,241
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	001	4	6/20/2024	SUPPLEMENT FOR EXPANSION	$66,951
														Subtotal = $548,192

Issue Date FY: 2023 ( Subtotal = $481,241 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	000	3	6/13/2023	NON-COMPETING CONTINUATION	$481,241
														Subtotal = $481,241

Issue Date FY: 2022 ( Subtotal = $481,241 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	000	2	5/23/2022	NON-COMPETING CONTINUATION	$481,241
														Subtotal = $481,241

Issue Date FY: 2021 ( Subtotal = $495,366 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Aging Research	000	1	8/4/2021	NEW	$495,366
														Subtotal = $495,366

Grand Total All Awards = $2,477,656

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Chemical approaches to selectively target beta-rich amyloids

Award Number: R01AG074570

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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